Our goal is to identify molecules involved in signalling during mammalian development, especially during the development of the central nervous system (CNS). We are taking two complementary approaches. In the first, we are investigating the developmental roles of neuropeptides, known intercellular signalling molecules. In the second, we are cloning genes defined by murine mutants affected in CNS development. As signalling molecules, neuropeptides are well characterized structurally but knowledge of their functional roles, especially in development, remains uncertain. Data for their involvement is largely circumstantial, based on their occurrence at ectopic sites (relative to their sites of expression in the adult) in late stages of development. We have begun comprehensive analyses of two systems. In the somatostatin system, we have introduced a null allele at the somatostatin locus into the mouse germline and are introducing disruption alleles at all five somatostatin receptor loci. In our study of endogenous opioids, we are introducing null alleles at the three loci (POMC, dynorphin, enkephalin) which encode these opioids. Recent observations of synergistic interactions between mutations underscore the importance of a systematic approach to the study of neuropeptides which allows the analysis of double mutants. These mutant mice will allow us to determine the physiological roles of neuropeptides and to define fundamental processes of development.